Pharmacological inhibition of Mint3 attenuates tumour growth, metastasis, and endotoxic shock

Author:

Sakamoto TakeharuORCID,Fukui Yuya,Kondoh YasumitsuORCID,Honda Kaori,Shimizu Takeshi,Hara Toshiro,Hayashi Tetsuro,Saitoh Yurika,Murakami YoshinoriORCID,Inoue Jun-ichiroORCID,Kaneko ShuichiORCID,Osada HiroyukiORCID,Seiki Motoharu

Abstract

AbstractHypoxia-inducible factor-1 (HIF-1) plays essential roles in human diseases, though its central role in oxygen homoeostasis hinders the development of direct HIF-1-targeted pharmacological approaches. Here, we surveyed small-molecule compounds that efficiently inhibit the transcriptional activity of HIF-1 without affecting body homoeostasis. We focused on Mint3, which activates HIF-1 transcriptional activity in limited types of cells, such as cancer cells and macrophages, by suppressing the factor inhibiting HIF-1 (FIH-1). We identified naphthofluorescein, which inhibited the Mint3–FIH-1 interaction in vitro and suppressed Mint3-dependent HIF-1 activity and glycolysis in cancer cells and macrophages without evidence of cytotoxicity in vitro. In vivo naphthofluorescein administration suppressed tumour growth and metastasis without adverse effects, similar to the genetic depletion of Mint3. Naphthofluorescein attenuated inflammatory cytokine production and endotoxic shock in mice. Thus, Mint3 inhibitors may present a new targeted therapeutic option for cancer and inflammatory diseases by avoiding severe adverse effects.

Funder

Japan Agency for Medical Research and Development

Ministry of Education, Culture, Sports, Science and Technology

the Kobayashi Foundation for Cancer Research

Publisher

Springer Science and Business Media LLC

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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